Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Interferes with Extracellular Signal-regulated Kinase (ERK) and Jun NH2-terminal Kinase (JNK) Activation, but Does Not Affect Phosphorylation of T Cell Receptor ζ and ZAP70

The costimulatory molecules B7-1 and B7-2 regulate T cell activation by delivering activation signals through CD28 and inhibitory signals through CTLA4. Graft-vs-host disease (GVHD) is caused by activated donor T cells. Previously, we showed that CD28-deficient donor T cells induced less-severe GVHD than wild-type donor T cells, suggesting that CD28 signals exacerbate GVHD. In this paper we demonstrate that CTLA4 signals attenuate the severity of GVHD. Targeting the CD28 receptor with a specific mAb modulates the receptor in vivo, inhibits donor T cell expansion, and prevents GVHD. CTLA4 signaling was necessary for this effect because treatment with a soluble ligand that blocks binding of B7 to both CD28 and CTLA4 did not prevent GVHD as effectively as anti-CD28 mAb. These results support the current model of T cell costimulation in which CD28 signals amplify GVHD while CTLA4 signals inhibit GVHD, providing evidence that selective targeting of CD28 might be a better therapeutic strategy for inducing immunological tolerance than blocking the ligands for both CD28 and CTLA4.

Section: Discussionsupporting

confidence: 82%

CD28-Specific Antibody Prevents Graft-Versus-Host Disease in Mice

Bidwell

Martin

et al. 2000

“…CTLA-4, like CD28, binds to members of the B7 family, but has an inhibitory effect on T cell activation (25,26), making CTLA-4 a logical candidate for initiating anergy. Further, the defects in anergic cells appear to be similar to the acute effects of CTLA-4 cross-linking, namely blockade of proliferation and IL-2 production (25,26), reduction of mitogen-activated protein kinase activation (27,28), and inhibition of AP-1 and NF-B activity (29). Indeed, administration of anti-CTLA-4 blocking Abs during anergy induction appears to inhibit the induction of T cell hyporesponsiveness in several systems (20, 21, 30 -32), and these observations are the basis for models invoking CTLA-4 signal transduction in the induction of anergy.…”

Section: Induction Of T Cell Anergy In Thementioning

confidence: 93%

Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction

Frauwirth

Alegre

Thompson

2000

Immunologic tolerance in T lymphocytes is maintained through both thymic and peripheral contributions. One peripheral tolerance mechanism is the induction of T cell anergy, a form of nonresponsiveness resulting from incomplete T cell activation, such as stimulation through the TCR in the absence of costimulation. Recent reports have suggested that engagement of the inhibitory receptor CTLA-4 by its B7 ligand is critical for the initiation of anergy. We tested the importance of CTLA-4 in anergy induction in primary T cells with an in vitro anergy system. Using both CTLA-4/B7-blocking agents and CTLA-4-deficient T cells, we found that T cell anergy can be established in the absence of CTLA-4 expression and/or function. Even in the absence of CTLA-4 signal transduction, T cells activated solely through TCR ligation lose the ability to proliferate as a result of autocrine IL-2 production upon subsequent receptor engagement. Thus, CTLA-4 signaling is not required for the development of T cell anergy.

“…However, CTLA-4 has also been shown to mediate downregulation of T cell responses in the absence of CD28 (37,38), indicating that CTLA-4 must have signaling properties independent of its effects on CD28. In particular, CTLA-4 cross-linking has been shown to reduce activation of the mitogen-activated protein kinase pathway induced following TCR stimulation in the absence of a second signal (39).…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 Gene Polymorphism at Position 49 in Exon 1 Reduces the Inhibitory Function of CTLA-4 and Contributes to the Pathogenesis of Graves’ Disease

Kouki

Sawai

Gardine

et al. 2000

466

337

Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28. CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association of Graves’ disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity. In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared from GD (n = 45), Hashimoto’s thyroiditis (HT) (n = 18), and NC (n = 43). There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% in NC), and significantly fewer patients with the A/A allele (17.8% vs 34.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose-dependent manner. Augmentation induced by CTLA-4 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC). Although PBMC from individuals with the G/G alleles showed 132% augmentation, those with the A/A alleles showed 193% augmentation (p = 0.019). CTLA-4 polymorphism affects the inhibitory function of CTLA-4. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.